Abstract
The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described.Part 1 of this two-part series details the design and execution of a classical resolution to generate atropisomer M-l from a racemic precursor(rac-l).In parallel,the team sought to develop a racemization process to enable recycling of the classical resolution waste stream and maximize productivity and sustainability.Computational and experimental methods revealed a high barrier to rotation(ca.42 kcal/mol) prompting the design of a high-temperature(>300 ℃) racemization protocol for recovery of the racemic compound.Described herein are the determination of the barrier to rotation,optimization of conditions to enable racemization,proof-of-concept for a continuous-flow process to execute the process,and kilogram-scale demonstration,including(1) recovery of the undesired atropisomer as a crystalline solid from the classical resolution waste stream,(2) thermal racemization by a high-temperature continuous-flow process,and(3) isolation of the racemic compound by crystallization directly from the reaction stream.
NSTL